The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration
The visual cycle refers to a series of biochemical reactions of retinoids in ocular tissues and supports the vision in vertebrates. The visual cycle regenerates visual pigments chromophore, 11-cis-retinal, and eliminates its toxic byproducts from the retina, supporting visual function and retinal ne...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9560169/?tool=EBI |
| _version_ | 1811237411630350336 |
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| author | Yuhong Wang Xiang Ma Parthasarathy Muthuraman Arun Raja Aravindan Jayaraman Konstantin Petrukhin Christopher L. Cioffi Jian-Xing Ma Gennadiy Moiseyev |
| author_facet | Yuhong Wang Xiang Ma Parthasarathy Muthuraman Arun Raja Aravindan Jayaraman Konstantin Petrukhin Christopher L. Cioffi Jian-Xing Ma Gennadiy Moiseyev |
| author_sort | Yuhong Wang |
| collection | DOAJ |
| description | The visual cycle refers to a series of biochemical reactions of retinoids in ocular tissues and supports the vision in vertebrates. The visual cycle regenerates visual pigments chromophore, 11-cis-retinal, and eliminates its toxic byproducts from the retina, supporting visual function and retinal neuron survival. Unfortunately, during the visual cycle, when 11-cis-retinal is being regenerated in the retina, toxic byproducts, such as all-trans-retinal and bis-retinoid is N-retinylidene-N-retinylethanolamine (A2E), are produced, which are proposed to contribute to the pathogenesis of the dry form of age-related macular degeneration (AMD). The primary biochemical defect in Stargardt disease (STGD1) is the accelerated synthesis of cytotoxic lipofuscin bisretinoids, such as A2E, in the retinal pigment epithelium (RPE) due to mutations in the ABCA4 gene. To prevent all-trans-retinal—and bisretinoid-mediated retinal degeneration, slowing down the retinoid flow by modulating the visual cycle with a small molecule has been proposed as a therapeutic strategy. The present study describes RPE65-61, a novel, non-retinoid compound, as an inhibitor of RPE65 (a key enzyme in the visual cycle), intended to modulate the excessive activity of the visual cycle to protect the retina from harm degenerative diseases. Our data demonstrated that (±)-RPE65-61 selectively inhibited retinoid isomerase activity of RPE65, with an IC50 of 80 nM. Furthermore, (±)-RPE65-61 inhibited RPE65 via an uncompetitive mechanism. Systemic administration of (±)-RPE65-61 in mice resulted in slower chromophore regeneration after light bleach, confirming in vivo target engagement and visual cycle modulation. Concomitant protection of the mouse retina from high-intensity light damage was also observed. Furthermore, RPE65-61 down-regulated the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway, decreased the inflammatory factor, and attenuated retinal apoptosis caused by light-induced retinal damage (LIRD), which led to the preservation of the retinal function. Taken together, (±)-RPE65-61 is a potent visual cycle modulator that may provide a neuroprotective therapeutic benefit for patients with STGD and AMD. |
| first_indexed | 2024-04-12T12:23:51Z |
| format | Article |
| id | doaj.art-f92103a0288b474398c242da5fb00690 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T12:23:51Z |
| publishDate | 2022-01-01 |
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| spelling | doaj.art-f92103a0288b474398c242da5fb006902022-12-22T03:33:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-011710The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degenerationYuhong WangXiang MaParthasarathy MuthuramanArun RajaAravindan JayaramanKonstantin PetrukhinChristopher L. CioffiJian-Xing MaGennadiy MoiseyevThe visual cycle refers to a series of biochemical reactions of retinoids in ocular tissues and supports the vision in vertebrates. The visual cycle regenerates visual pigments chromophore, 11-cis-retinal, and eliminates its toxic byproducts from the retina, supporting visual function and retinal neuron survival. Unfortunately, during the visual cycle, when 11-cis-retinal is being regenerated in the retina, toxic byproducts, such as all-trans-retinal and bis-retinoid is N-retinylidene-N-retinylethanolamine (A2E), are produced, which are proposed to contribute to the pathogenesis of the dry form of age-related macular degeneration (AMD). The primary biochemical defect in Stargardt disease (STGD1) is the accelerated synthesis of cytotoxic lipofuscin bisretinoids, such as A2E, in the retinal pigment epithelium (RPE) due to mutations in the ABCA4 gene. To prevent all-trans-retinal—and bisretinoid-mediated retinal degeneration, slowing down the retinoid flow by modulating the visual cycle with a small molecule has been proposed as a therapeutic strategy. The present study describes RPE65-61, a novel, non-retinoid compound, as an inhibitor of RPE65 (a key enzyme in the visual cycle), intended to modulate the excessive activity of the visual cycle to protect the retina from harm degenerative diseases. Our data demonstrated that (±)-RPE65-61 selectively inhibited retinoid isomerase activity of RPE65, with an IC50 of 80 nM. Furthermore, (±)-RPE65-61 inhibited RPE65 via an uncompetitive mechanism. Systemic administration of (±)-RPE65-61 in mice resulted in slower chromophore regeneration after light bleach, confirming in vivo target engagement and visual cycle modulation. Concomitant protection of the mouse retina from high-intensity light damage was also observed. Furthermore, RPE65-61 down-regulated the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway, decreased the inflammatory factor, and attenuated retinal apoptosis caused by light-induced retinal damage (LIRD), which led to the preservation of the retinal function. Taken together, (±)-RPE65-61 is a potent visual cycle modulator that may provide a neuroprotective therapeutic benefit for patients with STGD and AMD.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9560169/?tool=EBI |
| spellingShingle | Yuhong Wang Xiang Ma Parthasarathy Muthuraman Arun Raja Aravindan Jayaraman Konstantin Petrukhin Christopher L. Cioffi Jian-Xing Ma Gennadiy Moiseyev The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration PLoS ONE |
| title | The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration |
| title_full | The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration |
| title_fullStr | The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration |
| title_full_unstemmed | The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration |
| title_short | The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration |
| title_sort | novel visual cycle inhibitor rpe65 61 protects retinal photoreceptors from light induced degeneration |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9560169/?tool=EBI |
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